Traumatic brain injury (TBI) can lead to secondary injuries, including axon and myelin damage, which contributes to long-term neurological deficits. The positron emission tomography (PET) tracer [18F]3F4AP, a fluorinated derivative of the U.S. Food and Drug Administration (FDA)-approved drug 4-aminopyridine, selectively binds to voltage-gated potassium (KV) channels, offering a novel approach to assess TBI-related node of Ranvier disruption and demyelination. This study evaluated [18F]3F4AP PET in penetrating and non-penetrating TBI models. Either controlled cortical impact (CCI, penetrating) or concussive (non-penetrating) TBI models were used to induce TBI in mice. Dynamic PET imaging with [18F]3F4AP was performed at time points of 0, 3, 7, 14, and/or 28–31 days post-injury (dpi), with quantitative analyses comparing tracer uptake in injured versus control regions. Luxol fast blue staining was conducted to evaluate histological myelin loss. In the CCI model, [18F]3F4AP PET imaging demonstrated a 31% increase in tracer uptake at the injury site at 7 dpi, correlating with histological evidence of demyelination. Tracer uptake gradually declined over time, reflecting potential remyelination. The concussive TBI model showed a smaller and more diffuse increase in uptake at 7 dpi compared to CCI. [18F]3F4AP PET imaging effectively detects demyelination following TBI with a very high sensitivity to penetrating injuries. These findings highlight the potential of [18F]3F4AP as a valuable imaging biomarker for the assessment of TBI progression and/or therapeutic response. Further studies are warranted to explore its clinical applicability and comparison with other imaging modalities.
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